title: Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment.
abstract: This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC(50)) and was compared to the chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π-π or π-cationic interactions.
authors.affiliation: Charles University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry and Drug Control, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Marketa
authors.initials: M
authors.lastname: Komloova
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Anna
authors.initials: A
authors.lastname: Horova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Holas
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Dohnal
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000549:Ambenonium Chloride / Q000737:chemistry / Q000494:pharmacology; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D004491:Edrophonium / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009157:Myasthenia Gravis / Q000188:drug therapy*; D011485:Protein Binding; D011806:Quinolinium Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011806:Quinolinium Compounds; D011994:Recombinant Proteins; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D000549:Ambenonium Chloride; D004491:Edrophonium; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase